Myocardial Ischemia can be induced by mental stress in patients with coronary heart disease (CHD). Mental stress-induced ischemia is predictive of increased risk of adverse cardiac events, and its prognostic clinical significance has been established over and above ischemia induced during exercise stress testing. Although mental stress testing holds much promise as a clinical tool, the mechanisms underlying mental stress ischemia need to be identified, and the prognostic value of stress-induced perturbations in other biomarkers of cardiac risk are unknown. This application was developed in response to RFA-HL-09-001, as an ancillary study to an upcoming clinical trial that includes the assessment of mental stress induced myocardial ischemia in CHD patients, both before and after a stress management intervention. The proposed ancillary study extends the parent study by focusing on transient impairment of vascular endothelial function and autonomic regulation of the heart during mental stress testing. Transient impairment in these cardiovascular regulatory systems may be responsible for the manifestation of ischemic activity, and also may contribute independently to risk of adverse clinical outcomes. Parasympathetic cardiac control, indexed by heart rate variability (HRV), is attenuated during mental stress, resulting in cardiac electrical instability and heightened risk of events. Mental stress also has been shown to have an adverse impact on vascular endothelial function as measured by flow-mediated dilation (FMD). CHD patients are characterized by endothelial dysfunction, even under resting conditions, and further compromise of this critical vascular regulatory mechanism, especially in the coronary vessels, may provoke mental stress ischemia and increase the risk for cardiac events. The proposed ancillary study is designed to evaluate whether these stress biomarkers are related to the occurrence of myocardial ischemia and to assess their prognostic value. By building upon the infrastructure of the parent clinical trial, which includes a clinical follow-up phase, a cost-effective approach to addressing the following research hypotheses is possible: (i) Mental stress-induced impairment of HRV and FMD will predict the occurrence of mental stress ischemia; (ii) Mental stress-induced impairment of HRV and FMD will predict adverse cardiovascular outcomes, and; (iii) a stress management intervention will result in improved HRV and FMD response to mental stress. The data generated by the ancillary study will have important clinical significance by advancing the use of mental stress testing for risk stratification in cardiac patients. PUBLIC HEALTH RELEVANCE: Coronary Heart Disease (CHD) is a significant health problem in the United States and throughout the world, and is the leading cause of death for men and women in the US. This study is designed to develop mental stress biomarkers that will refine risk stratification in CHD, and provide clinicians with assessment tools that will better equip them to optimize patient management.